Legube Gaëlle, Linares Laetitia K, Tyteca Sandrine, Caron Cécile, Scheffner Martin, Chevillard-Briet Martine, Trouche Didier
Laboratoire de Biologie Moléculaire Eucaryote, UMR 5099, CNRS and Université Paul Sabatier, IEFG (IFR 109), 118 Route de Narbonne, Université Paul Sabatier, 31062 Toulouse, France.
J Biol Chem. 2004 Oct 22;279(43):44825-33. doi: 10.1074/jbc.M407478200. Epub 2004 Aug 13.
The histone acetyl transferase Tip60 (HTATIP) shares many properties with the tumor suppressor p53 (TP53). Both proteins are involved in the cellular response to DNA damage, are subjected to proteasomal digestion following Mdm2-mediated ubiquitination, and accumulate after UV irradiation. We found here that knock-down of Tip60 affects the p53-dependent response following actinomycin D treatment, most likely because it inhibits p21 (CDKN1A) accumulation. Moreover, Tip60 is required for p53 to activate the endogenous p21 promoter, suggesting that it functions as a p53 co-activator. However, we also found that knock-down of Tip60 increases the turnover rate of p53 under normal growth conditions. Tip60 interferes with Mdm2-mediated degradation of p53, probably because it affects its subcellular localization. Taken together, our results suggest that Tip60 plays a double role in the p53 pathway: under normal growth conditions, Tip60 contributes to maintain a basal pool of p53 by interfering with its degradation; following DNA damage, Tip60 functions as p53 co-activator. That these two distinct roles are linked during the p53-dependent response is an attractive hypothesis.
组蛋白乙酰转移酶Tip60（HTATIP）与肿瘤抑制因子p53（TP53）具有许多共同特性。这两种蛋白都参与细胞对DNA损伤的反应，在Mdm2介导的泛素化后会被蛋白酶体消化，并在紫外线照射后积累。我们在此发现，敲低Tip60会影响放线菌素D处理后p53依赖的反应，很可能是因为它抑制了p21（CDKN1A）的积累。此外，p53激活内源性p21启动子需要Tip60，这表明它作为p53的共激活因子发挥作用。然而，我们还发现，在正常生长条件下敲低Tip60会增加p53的周转速率。Tip60干扰Mdm2介导的p53降解，可能是因为它影响了p53的亚细胞定位。综上所述，我们的结果表明Tip60在p53途径中发挥双重作用：在正常生长条件下，Tip60通过干扰p53的降解来维持其基础水平；在DNA损伤后，Tip60作为p53的共激活因子发挥作用。在p53依赖的反应过程中，这两种不同的作用相互关联，这是一个很有吸引力的假设。
